Use of 15-deoxyspergualin for the treatment of hyperreactive inflammatory diseases and autoimmune diseases

ABSTRACT

The invention describes the use of deoxyspergualin (DSG) or an analogue thereof for the preparation of a medicament for the treatment of and/or prophylaxis against hyperreactive inflammatory diseases and autoimmune diseases, wherein the treatment is performed in cycles.

The invention relates to the use of deoxyspergualin or analogues thereoffor the preparation of a medicament for the treatment of hyperreactiveinflammatory diseases, as vasculitis, and autoimmune diseases.

BACKGROUND OF THE INVENTION

Hyperreactive inflammatory diseases are characterized in that the bodyhyperreacts to nonspecific stimuli with an uncontrolled inflammationreaction. This inflammatory reaction (hyperreactivity) causespathological changes leading to the onset of the disease and its chronicestablishment. Concerning a definition and examples of hyperreactiveinflammatory diseases reference is made to EP-0 673 646, explicitlyincorporated herein. Vasculitis is an example of such a hyperreactiveinflammatory disease.

A general approach to vasculitis nomenclature and a set of definitionswas agreed by consensus (Jennette et al., 1994, “Nomenclature ofsystemic vasculitides. Proposal of an international consensusconference” Arthritis and Rheumatism, 37, 187-92), and is incorporatedherein by reference. According to this nomenclature, the distinctionbetween the various forms of vasculitis depends principally on the sizeof vessel affected with recognition of characteristic features. Thus,the term vasculitis encompasses small vessel vasculitis (Wegener'sgranulomatosis, Churg-Strauss syndrome, microscopic poly-angiitis,Henoch-Schönlein purpura, essential cryoglobulin-aemic angiitis),medium-sized vessel vasculitis (cutaneous leucocytoclastic angiitis) andlarge vessel vasculitis (Poly-arteritis nodosa, Kawasaki's disease,Giant cell (temporal) arteritis, Takayasu's arteritis). The salientfeatures are illustrated in: “Oxford Textbook of Clinical Nephrology”,2nd edition (1998), Vol. 2, Chapter 4.5, incorporated herein byreference. See e.g. page 880, Table 1, for a short listing of theclassification.

The clinical presentation of vasculitis is very diverse; it may bepresent as a primary disease or be associated with other diseases;vessels of different sizes may be affected in a single patient. Theaetiology and pathogenesis are unknown in the vast majority of patientswith vasculitis.

It was discovered that a certain spectrum of the diseases is associatedwith anti-neutrophil cytoplasmic antibodies, called ANCA. It is nowclear that they are not only associated with Wegener's granulomatosisbut also closely associated with microscopic polyangiitis andrenal-limited vasculitis (i.e. isolated focal necrotizingglomerulonephritis), although these findings are more heterogenous thanin Wegener's granulomatosis.

Autoimmune diseases are characterized by humoral, complement orcell-mediated immunity to constituents of the body's own tissues causinga clinical abnormality. As used herein, these tissues may also beallografts or xenografts, and graft-versus-host disease (GvHD) isconsidered an autoimmune disease for the purpose of this disclosure.Examples of autoimmune diseases are: collagenoses, vasculitides,arthritis, granulomatoses, organ specific autoimmunopathies as MorbusCrohn, ulcerative colitis and GvHD. In many diseases, autoimmunemechanisms are at least suspected as the molecular cause of disease.Various animal models of human autoimmune diseases exist and are used totest possible treatments. The diseases which may be treated according tothe invention also encompass malignant diseases of the immune system aschronic immuno-proliferative syndrome, monoclonal gammopathies, MorbusHodgkin and Non-Hodgkin-Lymphoma and chronic proliferative CD8-celldisease. The diseases which may be treated according to the inventiongenerally encompass those mentioned in Peter/Pichler, “KlinischeImmunologie”, 2nd ed., Urban & Schwarzenberg, 1996, p. X-XIV (Teil CKlinik).

Therapies for many hyperreactive inflammatory diseases and autoimmunediseases have to be regarded as insufficient. In many instances this isdue to severe side effects of the medicaments used. For example, forhyperreactive inflammatory diseases as Alzheimer's disease, pancreatitisand sepsis, there are no adequate treatments.

Regarding vasculitis, early attempts of treatment include the use oforal corticosteroids (OCS). Later, cyclophosphamid was added insteroid-resistant disease. A standard treatment of Wegener'sgranulomatosis, a form of vasculits, is a combination ofcyclophosphamide (CYC) and oral corticosteroids (OCS) Varioustherapeutic regimen including Prednisolone and cyclophosphamide orAzathioprine are disclosed in “Oxford Textbook for Clinical Nephrology,pp. 890”, referenced above. However, those therapies suffer from severaldrawbacks, including a relatively high number of therapy-resistantcases, a considerable relapse rate and side effects. For example,long-term treatment with CYC carries the risk of serious drug-relatedmorbidity and mortality. Also, in some patients even short-time exposureto cyclophosphamide leads to overt CYC-toxicity, e.g. marrowsuppression, toxic hepatitis or haemorrhagic cystitis and secondarycancers.

Similarly, efficient therapies for autoimmune diseases involving littleor no side effects are rare or, in most cases, absent.

Therefore, there is a continued need for improved treatments ofhyperreactive inflammatory diseases and autoimmune diseases.

It was now unexpectedly found that 15-deoxyspergualin (DSG) or analoguesthereof show a high efficiency in the treatment of hyperreactiveinflammatory diseases and autoimmune diseases when the treatment isperformed in treatment cycles.

DSG is a synthetic derivative of spergualin, a natural product isolatedfrom Bacillus laterosporus. It was originally described as havingantitumor activity, and subsequently was found to possessimmunosuppressive properties in experimental transplantation. Inadditional studies, DSG has demonstrated immunosuppressive activity inmany animal models of transplant rejection. For clinical humantransplantation, the safety and effectiveness of DSG treatment wereproved in kidney graft recipients. Moreover, DSG showed animmunosuppressive effect in animal models of autoimmune diseases (C.Odaka et al., Immunology, 95, 370-376, 1998) and hyperreactiveinflammatory diseases (EP-0 673 646).

SUMMARY OF THE INVENTION

In accordance with one aspect of the present invention, a novel methodfor preventing, stabilising or causing the regression of hyperreactiveinflammatory diseases, including vasculitis, and autoimmune diseases isdisclosed. The method comprises the administration of a therapeuticallyeffective amount of a component selected from the group consisting of15-deoxyspergualin or its derivatives or analogues to a mammalianspecies in need of such treatment in two or more treament cycles.

As used herein, autoimmune diseases as defined above also encompassdiseases in which the immunity is directed to constituents of tissues onallografts or xenografts, and, thus, graft-versus-host disease (GvHD).It also includes diseases in which autoimmune mechanisms are involved inthe pathogenesis.

The term “hyperreactive inflammatory disease” is used as defined in EP-0673 646, incorporated herein by reference. Vasculitis is an example of ahyperreactive inflammatory disease and is defined as indicated above andin the “Oxford Textbook of Clinical Nephrology”, 1998, Chapter 4.5(referenced above) and in: Jennette et al., 1994, “Nomenclature ofsystemic vasculitides. Proposal of an international consensusconference” Arthritis and Rheumatism, 37, 187-92, both explicitlyincorporated herein by reference. Malignant diseases of the immunesystem (see Peter/Pichler, above, for examples) may also be treatedaccording to the invention.

The phrase “preventing” a disease as used in the present applicationrefers to partially or fully inhibiting the development or progressionof disease.

The severeness and remission of the disease is defined primarily byclinical judgement. In addition, the severeness of vasculitis iscommonly defined using the Birmingham Vasculitis Activity Score. (BVAS)(Luqmani et al., Baillieres Clin. Rheumatol. (1997) 11(2):423-446).

DETAILED DESCRIPTION OF THE INVENTION

The methods of the present invention can be used for preventing,stabilizing or causing the regression of hyper-reactive inflammatorydiseases and autoimmune diseases.

In accordance with the present invention, various materials can be usedin treating these diseases. Preferred materials include15-deoxyspergualin (DSG) and analogues thereof. As used herein,“analogues” refers also to related compounds and derivatives of DSG andspergualin. Such compounds, which may be used in the present invention,are disclosed, inter alia, in EP-0 701 817, EP-0 669 316, EP-0 600 762,EP-0 212 606, EP-0 213 526, EP-0 347 820, EP-0 105 193, EP-0 241 797,EP-181 592, WO94/0414, WO96/24579, EP-0 743 300, EP-0 765 866, EP-0 349297, WO 99/03504 and German Patent application No. 35 06 330.

In particular, but not exclusively, compounds characterized by thefollowing formula (I) may be used:

wherin Y is an alkylene group having an even number of from 4 to 12carbons, preferably 6 to 10 carbons, or a meta or para mono-dialkylenephenyl radical substituent group, having in total 2 to 5 carbons in thealkylene residue (S), preferably 2 to 4 carbons, and X is an alkyleneradical having 1 to 5 carbons, preferably 1 to 3 carbons, which may havehydroxy, methoxy or hydroxymethyl group at the alpha-or beta-position asa substituent, or NH—X—CO— is an amino acid residue, especially Gly,L-His, L- and D-Ser, gamma-ABA and DL-HABA.

Furthermore, preferred compounds are characterized by the formula (II):

wherein: A is a single bond, —CH₂—, —CH₂—O—, —CH₂—NH—, —CH—(OH)—, —CHF—or —CH—(OCH₃)—; and n is 6 or 8.

Also preferred are compounds of the formula (III):

wherein: n is 6 or 8; A means a single bond, —CH₂—, —CH(OH)—, —CHF—,—CH—(OCH₃)—, —CH₂NH— or —CH₂—O— and its addition salts.

Two specific examples of useful derivatives of DSG are represented byformulae (IV) and (V), respectively:

15-deoxyspergualin and the process for its preparation is described inU.S. Pat. Nos. 4,518,532 and 4,525,299 to Umezawa et al., while U.S.Pat. No. 4,851,446 to Umezawa et al., describes an immunosuppressingmethod comprising the administration of 15-deoxyspergualin and relatedcompounds. The '299-and '466-patents are each incorporated herein byreference thereto.

According to a preferred embodiment of the present invention, DSG or ananalogue or derivative thereof is administered subcutaneously. Thus, itwas unexpectedly found that, in contrast to other immunosuppressantscommonly used, DSG can be administered by subcutaneous injection withoutlocal complications and is efficient to reach a systemically effectiveconcentration within short time. The feasability and effectivity of thismode of administration was even more surprising, as the informationsheet on Gusperimus hydrochloride preparation (Spanidin) Inj. of NipponKayaku Co. Ltd., Japan, of April 1994, recommends an intravenousinfusion over a time period of 3 hours.

According to the present invention, the treatment with DSG or ananalogue thereof is performed in two or more treatment cycles. Onetreatment cycle is defined as a series of subsequent days ofadministration of DSG or its analogue. It is understood that the term“treatment cycle” as used herein also encompasses a series of subsequentadministrations (at least two) wherein the time period between twosubsequent administrations of the drug(s) is less than 24 hours or morethan 24 hours, for example 48 hours, as long as these subsequentadministrations form a treatment “block” or “cycle” which is separatedfrom the next treatment cycle (block) by a time period which isconsiderably longer than the time period between two subsequentadministrations within one treatment cycle. However, the latter timeperiod is preferably less than 48 hours, in particular between 12 and 24hours.

It has been surprisingly found that the sequence of treatment cyclesinterrupted by interphases in which no drug is administered is moreefficient than a continuous administration (i.e. not in cycles). It isassumed, though the invention is not limited to a theoretical mechanism,that the multi-cycle treatment may provide a progressiveimmunomodulatory effect on the immune cell populations. This may beachieved by the repeated recovery (maturation and differentiation fromprogenitor cells) and selection of regulative or properly regulated cellpopulations. Cell populations directly or indirectly involved in thepathogenesis may be eliminated or otherwise inactivated during theserepeated modulations.

According to a preferred embodiment of the present invention, atreatment cycle lasts at least for 5 days, preferably at least about 7days, more preferably at least about 10 days, in particular at leastabout 14 days. The latter time period is preferred in order to make surethat all activated mature cells and all cells maturating during thistime period are affected. According to a preferred embodiment, atreatment cycle lasts about 18 to 21 days, however, longer cycles may beused.

According to another preferred embodiment of the present invention, eachcycle of treatment is aiming at a concentration of white blood cells of3.000 to 4.000/μl in the peripheral blood. Thus, the white blood cellcount of the patient is routinely determined and the decrease in whiteblood cells is monitored. As soon as the white blood cell count hasdropped to the range from 1.000 to 5.000/μl, preferably from 2.500 to5.000/μl, and in particular from 3.000 to 4.000/μl, the treatment isstopped to allow the concentration of white blood cells to recover to atleast about the range from 4.000 to 8.000/μl.

It has been surprisingly found that the efficiency of the treatment maybe also optimized by monitoring the level of granulocytes, and inparticular neutrophils (in addition to or instead of white blood cells)in the peripheral blood of the patient and adjusting the duration of andinterphase between the treatment cycles accordingly Thus, according toanother preferred embodiment of the present invention the neutrophilcount of the patient is routinely determined and the decrease ofneutrophils monitored. The numbers may be determined from a completeblood count (hemogram) of a blood sample, counting erythrocytes,leucocytes (WBC), thrombocytes and reticulocytes as well as from adifferential blood count, performed by counting 100 nucleated cells in ablood smear. (A standard method may found in Pschyrembel, “KlinischesWörterbuch”, de Gruyter, p. 196 and 326.) When the level has dropped tothe range from about 500 to about 4000/μl blood, preferably from 1.000to 4.000/μl blood, in particular from 2.000 to 3.000/μl blood, the cycleis terminated. The levels of peripheral blood lymphocytes (T- andB-cells) is also decreased, but to a lesser extent. The concentration ofneutrophils is allowed to recover to at least about the range from 3.000to 6.000/μl before the next cycle is started.

Thus, it was surprisingly found that the decrease and recovery in thenumber of white blood cells, and particularly neutrophils, in theperipheral blood of the patients may be advantageously used as aparameter for optimisation of the cycle treatment. This correlation mayindicate that these cell populations are directly or indirectly (viaregulatory mechanisms) linked to the pathogenesis; however, thisassumption does not limit the present invention.

It is noted that throughout the prior art literature, the leucocytopeniainduced by DSG or analogues thereof has been described as an adverseside effect of the drug. In contrast, according to a preferredembodiment the present invention a controlled and defined decrease inleucocyte, and particularly in neutrophil counts, is even aimed at andmade use of, as it has been surprisingly found that these parametersallow the optimisation of a multi-cycle treatment of hyper-reactiveinflammatory diseases and autoimmune diseases.

It is known that the level of white blood cells and neutrophils,respectively, may vary from patient to patient. Thus, according to apreferred embodiment of the present invention, the duration and intervalof the treatment cycles are monitored and determined in accordance withthe percentual inhibition of white blood cells (WBC) or neutrophils,respectively. According to this preferred embodiment, a treatment cycleis aiming at a decrease (inhibition) of the WBC level of at least about20%. (In other words, at the end of the cycle, only 80% or less of theWBC are left.) An inhibition of WBC of about 50 to about 80% ispreferred. However, higher inhibition rates up to 95% or more may beused and may even be preferrable, as long as the remaining level of WBCis not critical to the patient. In other words, a severe decrease of WBClevel is preferred, the lower limit being a WBC level which is stilltolerable without causing health problems. Thus, the level of WBC (orneutrophils, see below) may be decreased to a WHO toxicity grade of 3-4(corresponding to app. 1000 WBC/μl or 500 neutrophils/μl).

Similarly, according to a preferred embodiment of the invention, thepercentual inhibition of neutrophils is monitored in order to determinethe duration and interval of the treatment cycles. Thus, a treatmentcycle may be aiming at an inhibition of neutrophils in peripheral bloodof at least 25%. A preferred inhibition rate is between 55% and 90%,however, higher inhibition rates may be used and even preferred. Asstated above, the lower limit is determined by the minimum level ofneutrophils tolerated without causing health problems to the patient(see above).

The preferred recovery of WBCs and neutrophils is as defined above (atleast to about the range from 4.000 to 8.000 WBC/μl or at least about3.000 to 6.000 neutrophils/μl).

According to a preferred embodiment, a dosage of at least 0.2 mg/kg bodyweight of the patient/day, preferably at least 0.3 mg/kg body weight ofthe patient/day may be advantageously used to induce a progressive andreproducible reduction of white blood cells in the patient within areasonable cycle time. According to a further preferred embodiment adosage of at least 0.5 mg DSG/kg body weight of the patient/day is used.

However, it may be preferable to use subcutaneous dosages of between0.01 or 0.05 to 0.2 mg/kg body weight/day, especially in cases when suchlower dosages lead to a better controllable and reasonably progressingdecrease of WBCs/neutrophils.

According to an embodiment of the invention, the time period between twotreatment cycles is between 4 to 20 days. However, in certain instances,depending on recovery of white blood cells and the other clinicalparameters the time period between two treatment cycles may be shorteror considerably longer. Preferably, the interphase between two treatmentcycles is between 10 days to five weeks, in particular between two andfour weeks.

According to a preferred embodiment, the following protocol may befollowed: in case the WBC count drops to 3.000/μl or less within lessthan 14 days, the cycle is terminated and the dosage of deoxyspergualinor its analogue is reduced in the subsequent treatment cycle (e.g. from0.5 mg/kg/d to 0.25 mg/kg/d). In case the WBC count drops to 3.000/μl orless between day 14 and day 21 of the treatment cycle, the cycle isterminated and the subsequent treatment cycle is performed with anidentical dosage. In case the WBC count has not dropped to 3.000/μl orless on day 21 of the cycle, the cycle is prolonged until such a WBCcount is reached, maximally up to four weeks. The interval between twotreatment cycles is generally about 14 days according to thisembodiment. However, in case a relapse or increased disease activityoccurs in the interval between two treatment cycles, the new treatmentcycle may be started within less than 14 days from the termination ofthe previous cycle, under the proviso that a WBC count of at least4.000/μl has been reached again.

According to an alternative embodiment, which may be preferred for lifethreatening cases and in patients suffering from a relapse or a severelyincreased activity of the disease, a dosage of about 5 mg/kg/d may beused intravenously (e.g. in a three hour slow infusion) until a WBCcount of 3.000/μl or less is reached, or a maximum of 10 days. Thetreatment cycle is then followed by a rest until at least 4.000 WBC/μlare reached again. Preferrably, the interval between two treatmentcycles is around 14 days, unless a relapse occurs within the interval.The cycle treatment may be continued with a reduced dosage of spergualinor an analogue thereof as soon as disease control has been achieved.

According to one preferred aspect of the invention DSG or an analoguethereof are used in the treatment of vaculitis, in particularANCA-associated vasculitis. It was found that the whole complex range ofclinical symptoms associated with vasculitis could be improved andeliminated. Thus, it was surprisingly found that after 2 to 6 cycles oftreatment with DSG or an analogue or derivative thereof a completeremission occured, since no acute or chronic disease activity waspresent. This is in contrast to the high relapse rate and incompleteremission observed with the standard therapy of cytotoxic agentscombined with steroids, for example of cyclophosphamid and oralcorticoids (OCS). Also, no toxic side effects occured in using DSG or ananalogue or derivative thereof.

Thus, according to a preferred embodiment, the treatment comprises atleast two, preferably at least three or four treatment cycles as set outabove. In many cases it was found that typically 6 to 12 cycles arepreferable.

According to another embodiment of the present invention, DSG or ananalogue or derivative thereof is used in combination with othercompounds known in the art to have a beneficial effect in the treatmentof the disease treated. In the case of vasculitis, for example, oralcorticosteroids (OCS) may be used. It was also found that when OCS aregiven concomittantly with the DSG treatment according to the presentinvention, the dose of OCS can be severly reduced, for example from 16mg/d to about 6 mg/d (corresponding to about 0.02 to about 0.08 mg/kgbody weight/d).

Similarily, in the case of various autoimmune diseases a combinationwith immunosuppressive drugs as corticosteroids may be used. The dosagescommonly used are apparent to a person skilled in the art.

The deoxyspergualin compounds set forth above are typically used in theform of a pharmaceutically acceptable salt. Any salt of inorganic ororganic acids may be used, as long as it is pharmacologicallyacceptable. Preferred examples include chloride or hydrochloride salts,especially the tri-hydrochloride salt. Examples of acceptable salts maybe found in WO99/03504, incorporated herein by reference.

Though subcutaneous administration is preferred, any other mode ofadministration may also be used. Thus, the medicament may be preparedfor a peroral, intravenous, intracutaneous, intraperitoneal, intrahecal,intraocular, ocular, buccal, nasal, percutaneous, cutaneous, topical,inhalative, intramuscular or rectal administration.

The clinically therapeutic dose of DSG and related compounds is fromabout 0.01 to about 100 mg/d/kg of patient body weight, preferably from0.1 to 5 mg/d/kg, and may be administered in single or divided doses.For oral administrations up to 500 mg/d/kg may be used.

The present invention can also be practised using DSG and relatedcompounds in a racemic mixture, as well as (+) and (−) isomers of DSG orits analogues.

In carrying out the methods of the present invention, the agent(s) usedmay be administered to humans, but also to other mammalian species, suchas monkeys, dogs, cats, rats etc.

The agent used for treatment may be incorporated in a conventionaldosage form, such as a tablet, capsule, elixier or injectable. The abovedosage forms will also include the necessary carrier material,excipient, lubricant, buffer, antibacterial, bulking agent (such asmannitol), antioxidans (e.g. ascorbic acid or sodium bisulfite), orother necessary or beneficial additives as well-known or apparent to aperson skilled in the art. Examples of excipients and carriers may befound in WO99/03504, incorporated herein by reference.

The following examples are further illustrative of the presentinvention. However, these examples are not intended to limit the scopeof the present invention.

EXAMPLE I

A 35 year old male patient with Morbus Wegener had been suffering fromprogressive and relapsing disease despite various forms ofimmunosuppressive treatments for many years. The diagnosis ofANCA-associated systemic vasculitis was histologically confirmed. Thepatient showed severe involvement of the upper respiratory tract despitemaintenance, immunosuppression. He also showed subglottic stenosisnecessitating trachystoma, glottic granulomata, saddle nose deformity,hoarseness, pansinusitis and otitis media sinistra with deafness. He hadreceived almost all therapeutical standard options for treatment ofvasculitis for which a beneficial effect has been described in theliterature.

Thus, he had received cyclophosphamide (CYC) and OCS (oralcorticosteroids), showing a toxic hepatitis after 4 weeks. The furthertreatment history had included Azathioprene (AZA), Mycophenolate Mofetil(MMF), ATG (anti-thymocyte-globuline), MTX (Methotrexate), IVG(intravenous immunoglobulins) and plasmapheresis, showing severalrelapses. The disease activity according to the BVAS beforeDSG-treatment was 12.

The DSG used was a Gusperimus hydrochloride preparation (100 mg/vial)(Spanidin inj.) of Nippon Kayaku Co. Ltd., Tokyo, Japan. The formulationalso contained 200 mg of lactose as an inactive ingredient. Thelyophilized DSG (100 mg) was reconstituted with physiological saline andadmininstered at 0.5 mg/kg/d subcutaneously over 19 days. During thistreatment cycle, the white blood cell count in peripheral blood droppedfrom 12.300 white blood cells (WBC)/μl on day 1 to 3.460 WBC/μL on day19. Treatment with DSG was discontinued and white blood cell countsrecovered to 9.600/μl on day 33. No side effects were observed. Thelevels of white blood cells and neutrophils were regularity monitored.It was observed that those levels reached a nadir a few days aftertermination of a treatment cycle and then recovered in an almostpredictable manner.

The second DSG-treatment cycle was started on day 33 and subcutaneousadministration of DSG was continued until day 52 (WBC count 3500/μl ).Following an treatment rest from day 52 to day 65 (WBC count 11.500/μl),a third treatment cycle was performed from day 66 to day 85 (WBC counts12.000/μl and 3800/μl, respectively).

Neutrophil counts were always in the range from 2000/μl to 3000/μl atthe termination of a cycle and above 4000/μl when the subsequent cyclewas started.

The first treatment cycle and the levels of white blood cells(leucocytes), lymphocytes and neutrophils are shown in FIG. 1. Theshaded area corresponds to the first cycle (DSG administration period).

The BVAS (Birmingham vasculitis activity score) during follow-up isshown in FIG. 2.

After the first two treatment cycles with DSG the patient experienced asignificant improvement of his clinical condition.

After the third cycle, complete remission occured as determined byclinical judgement and BVAS (=0). Moreover, it was possible to tapersteroids from initially 16 mg methyl-prednisolone (corresponding toabout 0.2 mg/kg body weight) to 6 mg (corresponding to about 0.08 mg/kgbody weight). During all treatment cycles, no adverse side effects ofDSG have been observed and the drug was well tolerated. This has notbeen possible in the past without provoking relapses.

In conclusion, this Example shows that the cycle treatment with DSG wasvery effective even in this therapeutically difficult patient.

EXAMPLE II

A 50 year old female with M. Wegener having ANCA-associated systemicvasculitis showed involvement of peripheral nerves, kidney, gut andeyes. The diagnosis of ANCA-associated systemic vasculitis was confirmedhistologically and immunologically.

The patient showed mononeuritis multiplex with palsies, necrotizingglomerulonephritis, stenosis of small bowel segments, sinusitis,serotympanon and episcleritis. She had also been given varioustreatments including CYC+OCS, AZA and MMF with frequent relapses.

Therefore, DSG was administered subcutaneously as described in Example I(0.5 mg/kg/d).

The two treatment cycles were 14 days and 21 days, respectively, andwere terminated at white blood cell counts in the range of 3000-4000/μl(neutrophil counts (2000-3000/μl). The levels of white blood cells andneutrophils were regularly monitored. Treatment cycles were started atwhite blood cell counts above 4000/μl, and neutrophil counts above3500/μl.

A complete remission was observed even after two treatment cycles(BVAS=0), starting from an initial BVAS of 19.

The BVAS (Birmingham vasculitis activity score) during follow up isshown in FIG. 2.

EXAMPLE III

MRL/lpr mice develop systemic lupus erythematosus (SLE)-like lesions.The disease is characterized by massive lymphadenopathy, development ofantibodies to self antigens, and glomerulonephritis. Therefore, thesemice offer a good model for autoimmune disease.

Male MRL/MpJ-lpr/lpr (MRL/lpr) mice were obtained from Charles RiverJapan (Atsugi, Kanagawa, Japan). The mice were maintained in specificpathogen-free conditions.

DSG was obtained and prepared as described in Example I.

DSG was administered from week 13 through week 20 (58 days):

(A) i.v. at daily doses of 1.5 mg/kg or

(B) in three treatment cycles of 10 days with 1.5 mg/kg DSG i.v. dailywith an interphase (no DSG) of 14 days after the first and second cycle.

Each treatment group (A and B) consisted of 10 mice. A set of controlMRL/lpr-mice (10) receiving saline were included.

At the end of the experiment (day 59), the weight of the lymph nodes,serum anti-DNA titer and BUN (blood urea nitrogen) were measured asdescribed by Nemoto, K. et al., J. Antibiotics, (1990), 1590-1591. Thelevels of white blood cells in peripheral blood were decreased both ingroups A and B to about 6.000/μl compared to about 18.000/μl in thecontrol group.

However, the mice of group B, treated according to the invention, showeda more pronounced reduction of weight of the mesenteric, axillary,elbow, inguinal, submaxillary and iliac lymph nodes as compared to groupA. Also, the BUN and the anti-DNA titer was at a significantly lowerlevel in group B as compared to group A.

Thus, the cycle treatment with DSG according to the invention in theearly phase of the autoimmune disease was superior to continuous dailyadministration of an equal dosage of DSG and was more efficient insuppressing the development of SLE-like lesions. This was even moresurprising, as the total amount of DSG administered in group B wasalmost half of that administered in group A.

1. A method for the treatment of a hyperreactive inflammatory disease ina patient which comprises administering an effective amount ofmedicament comprising deoxyspergualin (DSG) or a pharmaceuticallyacceptable salt thereof to said patient, whereby said administration isperformed in at least two treatment cycles and an interphase in which noDSG or salt thereof is administered between the cycles wherein thehyperreactive inflammatory disease is systemic lupus erthymatosus (SLE)in a patient which comprises administering a therapeutically effectiveamount of DSG or a pharmaceutically acceptable salt thereof to saidpatient to treat SLE, wherein each treatment cycle lasts from about 5days to about 21 days; and wherein the interphase lasts from 10 days to5 weeks.
 2. The method of claim 1, wherein the hyperrreactiveinflammatory disease is SLE and which comprises administering atherapeutically effective amount of DSG or a pharmaceutically acceptablesalt thereof to a patient who is refractory or intractable to 1)corticosteroid treatment and 2) treatment with at least one agentselected from the group consisting of cyclophosphamide, azathioprine,mycophenolate mofetil, anti-thymocyte-globin, methotrexate andimmunoglobulin to said patient.
 3. The method of claim 1, wherein thepatient is refractory or intractable to corticosteroid treatment.
 4. Themethod of claim 1, wherein at least one patient is refractory orintractable to treatment with at least one agent selected from the groupconsisting of cyclophosphamide, azathioprine, mycophenolate mofetil,anti-thymocyte-globin, methotrexate and immunoglobulin.
 5. The methodaccording to claim 2, wherein the medicament further comprises one ormore additional active compounds.
 6. The method according to claim 5,wherein the additional active compounds are selected from the groupconsisting of a corticosteroid, cyclophosphamide, azathioprine,mycophenolate mofetil, anti-thymocyte-globin, methotrexate andimmunoglobulin.
 7. The method according to claim 1, wherein themedicament comprising 15-deoxyspergualin or a pharmaceuticallyacceptable salt is administered subcutaneously.
 8. The method accordingto claim 1, wherein, at the conclusion of a treatment cycle, the patienthas a level of white blood cells (WBC) in peripheral blood of thepatient which is in a range from about 1,000 to about 5,000/μl blood. 9.The method according to claim 8, wherein the range is from about 2,000to 5,000/μl blood.
 10. The method according to claim 8, wherein therange is from about 3,000 to 4,000/μl blood.
 11. The method according toclaim 1, wherein, at the conclusion of a treatment cycle, the patienthas a level of neutrophils in the peripheral blood of patient which isin a range from about 500 to about 4,000/μl blood.
 12. The methodaccording to claim 11, wherein the range is from about B 1,000 to4,000/μl blood.
 13. The method according to claim 11, wherein the rangeis from about 2,000 to 3,000/μl blood.
 14. The method according to claim8 wherein the next treatment cycle is started when the level of whiteblood cells in peripheral blood of the patient has recovered to at leastabout 4,000/μl blood.
 15. The method according to claim 11, wherein thenext treatment cycle is started when the level of neutrophils in theperipheral blood of the patient has recovered to at least about 3,000/μlblood.
 16. The method according to claim 1, wherein, at the conclusionof each treatment cycle, the patient exhibits a decrease of WBC inperipheral blood of the patient of at least 20%.
 17. The methodaccording to claim 16, wherein the decrease is at least 50%.
 18. Themethod according to claim 16, wherein the decrease is at least 80%. 19.The method according to claim 1, wherein at the conclusion of eachtreatment cycle, the patient exhibits a decrease of neutrophils inperipheral blood of the patient of at least 25%.
 20. The methodaccording to claim 19, wherein the decrease is at least 50%.
 21. Themethod according to claim 19, wherein the decrease is at least 90%. 22.The method according to claim 1, wherein the interphase between at leasttwo of the treatment cycles is from two to four weeks.
 23. The methodaccording to claim 1, wherein the interphase between at least two of thetreatment cycles is about 14 days.
 24. The method according to claim 1,where, in case a relapse or increased disease activity occurs in theinterval between two treatment cycles, the new treatment cycle isstarted within less than 14 days from the termination of the previouscycle with the proviso that a WBC level in peripheral blood of at least4,000/μl blood has been reached again.
 25. The method according to claim1, wherein at least 3 or 4 cycles are performed.
 26. The methodaccording to claim 1, wherein a treatment cycle is terminated when thepatient has a level of WBC in peripheral blood of 3,000/μl blood or lesswithin 14 days from the start of the treatment cycle and the amount of15-deoxyspergualin or a pharmaceutically acceptable salt is reduced inthe subsequent treatment cycle.
 27. The method according to claim 1,wherein a treatment cycle is terminated when the patient has a level ofWBC in peripheral blood of 3,000/μl blood or less between 14 and 21 daysfrom the start of the treatment cycle and the amount of15-deoxyspergualin or a pharmaceutically acceptable salt in themedicament is identical in the subsequent treatment cycle.
 28. Themethod according to claim 1, wherein the medicament is administeredintravenously in an amount such that about 5 mg/kg/d of15-deoxyspergualin or a pharmaceutically acceptable salt is administeredto the patient until either (i) a WBC level in peripheral blood of 3,000μl blood or less is reached or (ii) 10 days from the beginning of thecycle have elapsed.
 29. The method according to claim 1, wherein atreatment cycle is prolonged for a period until a WBC level inperipheral blood of 3,000/μl blood or less is reached, provided that theperiod does not exceed four weeks.
 30. The method according to claim 1,wherein the amount of 15-deoxyspergualin or a pharmaceuticallyacceptable salt contained in the medicament is 0.01 mg to 100 mg/kg bodyweight of the patient.
 31. The method according to claim 30, wherein theamount of 15-deoxyspergualin or a pharmaceutically acceptable salt is0.1 to 5 mg/kg body weight of the patient.
 32. The method according toclaim 30, wherein the amount of 15-deoxyspergualin administered to thepatient is 0.5 mg/kg/d.
 33. The method according to claim 1, wherein theadministration of the medicament to the patient is intravenous,intracutaneous, intraperitoneal, intrathecal, intraocular, ocular,buccal, nasal, percutaneous, cutaneous, topical, inhalative,intramuscular or rectal.
 34. The method according to claim 1, whereinthe 15-deoxyspergualin or a pharmaceutically acceptable salt is agusperimus hydrochloride.